PROJECT SUMMARY This project focuses on the potential mucosal triggers that contribute to two autoimmune fibrotic disorders, IgG4-related disease and systemic sclerosis. In both these diseases, similar immune changes - especially the clonal expansion of cytotoxic CD4+ T cells and the infiltration of these cells into disease tissues are observed, activated B cells are seen in contact with these expanded T cells, and both diseases are characterized by striking similarities in the intestinal microbiome. Microbial metabolites from specific microbes could contribute to the expansion of cytotoxic CD4+ T cells and the activation of innate immune cells that contribute to fibrosis. We will examine whether intestinal microbial gene expression- metatranscriptomics - reveals differences between subsets of disease, comparing diffuse versus limited systemic sclerosis, and systemic sclerosis versus IgG4- related disease. We will also investigate whether metatranscriptomic differences can explain differential responsiveness to therapy. The possible contribution of microbial metabolites to immune cell differentiation will be examined and microbial antigens that activate host T cells will also be identified.